Heart failure is the only cardiovascular disease that is increasing in prevalence and the outlook for a patient with dilated heart failure remains dismal despite recent advances in therapy. The key abnormality is the major focus of this Project. We have shown that the amount of adenylyl cyclase (AC) sets a limit on cAMP production. We then showed that over-expression of AC increases cardiac contractile function in transgenic mice. When AC is expressed in the setting of murine cardiomyopathy, cardiac function and survival are improved. Finally, we recently demonstrated that cardiac AC expression can be increased in a manner that can be applied clinically-through intracoronary delivery of an adenovirus encoding AC. The effects on LV function and cAMP generating capacity after intracoronary delivery are long-lasting and not associated with deleterious effects. These studies were conducted using AC type VI, a major isoform in mammalian heart. Cardiac-directed expression of ACVI or ACVIII, an isoform more typically found in brain than heart, shows similar favorable effects on cardiac contractility. But ACVIII exhibits unique properties. For example, compared to ACVI, ACVIII is less responsive to beta-adrenergic receptor (betaAR) stimulation, a potential advantage in the setting high catecholamine levels associated with congestive heart failure. We propose a gene therapy for heart failure. First, we will perform the necessary toxicology studies and bridging preclinical studies to support a Phase1/Phase 2 clinical trial of ACVIII gene therapy for severe heart failure (completed in the first funding year). We then will perform the clinical trial using intracoronary delivery of an adenovirus encoding human ACVIII for the treatment of dilated Class III/IV congestive heart failure (completed mid-way through Year 3). In the later phase of the award we will study other genes that might increase contractility and favorably influence symptoms and survival in heart failure. These studies will provide preclinical data sufficient to support a second IND filing so that the second Phase 1/Phase 2 clinical trial could be conducted in Year 4 and 5. A prime candidate is sarcoplasmic reticulum Ca2+ ATPase (SERCA2a). Hypotheses: 1. Intracoronary delivery of an adenovirus encoding ACVIII will improve heart function and reduce symptoms in patients with Class III/IV congestive heart failure. 2. Intracoronary delivery of an adenovirus encoding Ca2+ ATPase (SERCA2a) will improve heart function and reduce symptoms in patients with Class III/IV congestive heart failure.